The possibility of contaminating medicinal products with other potentially active moieties is an ever-increasing risk in the production and use of pharmaceutical products. There appears to be a growing practice of manufacturing different medicinal products in shared facilities presenting the potential for cross contamination. Also, for those medicinal products requiring the use of a delivery system, there has always been the risk of contamination of the medicinal product with leachable materials during contact with the device.

In 2012 a draft guidance document on the setting of health based exposure limits (HBELs) of such contaminants was produced by the European Medicines Agency (EMA) which was then adopted in 2014 (EMA/CHMP/CVMP/SWP/169430/2012) by both the Committee for Medicinal Products for Human Use (CHMP) and also the Committee for Medicinal Products for Veterinary Use (CVMP).

The EMA guidance document gives details on the calculation of HBELs, specifically Permitted Daily Exposures (PDEs) in conjunction with the ICH guideline on Impurities (Q3C(R6)). The objective of the guideline is to recommend an approach to review and evaluate pharmacological and toxicological data of individual active substances and thus enable determination of threshold levels in the form of PDEs.

The determination of a PDE involves:

  • Hazard identification by reviewing all relevant data;
  • Identification of key toxicological effects;
  • Determination of the no-observed-adverse-effects level (NOAEL of the findings that are considered to be key toxicological effects); and
  • Use of several adjustment factors to account for various uncertainties.

  • The key factors in applying this process are:

  • Having a robust literature searching procedure that will ensure the capture of all relevant references from which appropriate Points of Departure (PoD) can be identified;
  • Having the appropriate experience and knowledge to interpret toxicological data, identify key toxicological effects and conduct a weight of evidence approach in the selection of the key PoD;
  • Being able to modify the PoD dose level if required in order to express the PoD in appropriate units depending on the exposure scenario; and
  • Being able to provide a full justification and reasoning behind the selection of the various adjustment factors

  • wca have significant experience in all aspects of the process for derivation of HBELs for a variety of substances including leachables/extractables in medical devices, pharmaceuticals, drinking water contaminants and components of various therapeutic and non-therapeutic mixtures. For enquiries or for further information on how we can help you, please contact us.

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